Neutrophil elastase induces mucus cell metaplasia in mouse lung
Neutrophil elastase induces mucus cell metaplasia in mouse lung
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DOI：
10.1152/ajplung.00140.2004
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发表时间：
2004-12-01
影响因子：
4.9
通讯作者：
Foster, WM
中科院分区：
文献类型：
--
作者：
Voynow, JA;Fischer, BM;Foster, WM
浅表气道上皮中的杯状细胞增生是慢性支气管炎和囊性纤维化的标志性病理特征。在这些慢性炎症性气道疾病中，上皮衬里液中存在高浓度的中性粒细胞弹性蛋白酶（NE）。据报道，NE 可在体外触发粘蛋白分泌并增加粘蛋白基因表达。我们假设，体内长期暴露于小鼠气道的去甲肾上腺素会诱导杯状细胞化生。在第 1、4 和 7 天，雄性 Balb/c（6 周龄）小鼠气管内吸入人 NE（50 杯）或 PBS 盐水。在第 8、11 和 14 天，获得肺组织用于组织学分析和支气管肺泡灌洗 (BAL) 样本用于细胞计数和细胞因子水平。 NE 在第 8、11 和 14 天诱导 Muc5ac mRNA 和蛋白表达以及杯状细胞化生。这些细胞变化是蛋白水解活性的结果，因为添加弹性蛋白酶抑制剂甲氧基琥珀酰 Ala-Ala-Pro-Val 氯甲基酮 (AAPV-CMK) 可阻断 NE 诱导的 Muc5ac 表达和杯状细胞化生。 NE 显着增加 BAL 中角质形成细胞衍生的趋化因子和 IL-5，并增加肺组织炎症和 BAL 白细胞计数。添加 AAPV-CMK 将这些炎症指标降低至控制水平。这些实验表明，NE 蛋白水解活性引发炎症过程，导致杯状细胞化生。
Goblet cell hyperplasia in the superficial airway epithelia is a signature pathological feature of chronic bronchitis and cystic fibrosis. In these chronic inflammatory airway diseases, neutrophil elastase (NE) is found in high concentrations in the epithelial lining fluid. NE has been reported to trigger mucin secretion and increase mucin gene expression in vitro. We hypothesized that chronic NE exposure to murine airways in vivo would induce goblet cell metaplasia. Human NE (50 mug) or PBS saline was aspirated intratracheally by male Balb/c (6 wk of age) mice on days 1, 4, and 7. On days 8, 11, and 14, lung tissues for histology and bronchoalveolar lavage (BAL) samples for cell counts and cytokine levels were obtained. NE induced Muc5ac mRNA and protein expression and goblet cell metaplasia on days 8, 11, and 14. These cellular changes were the result of proteolytic activity, since the addition of an elastase inhibitor, methoxysuccinyl Ala-Ala-Pro-Val chloromethylketone (AAPV-CMK), blocked NE-induced Muc5ac expression and goblet cell metaplasia. NE significantly increased keratinocyte-derived chemokine and IL-5 in BAL and increased lung tissue inflammation and BAL leukocyte counts. The addition of AAPV-CMK reduced these measures of inflammation to control levels. These experiments suggest that NE proteolytic activity initiates an inflammatory process leading to goblet cell metaplasia.